Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Jan 15;88(2):647–651. doi: 10.1073/pnas.88.2.647

Immunoglobulins from animal models of motor neuron disease and from human amyotrophic lateral sclerosis patients passively transfer physiological abnormalities to the neuromuscular junction.

S H Appel 1, J I Engelhardt 1, J García 1, E Stefani 1
PMCID: PMC50869  PMID: 1988960

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating human disease of upper and lower motoneurons of unknown etiology. In support of the potential role of autoimmunity in ALS, two immune-mediated animal models of motoneuron disease have been developed that resemble ALS with respect to the loss of motoneurons, the presence of IgG within motoneurons and at the neuromuscular junction, and with respect to altered physiology of the motor nerve terminal. To provide direct evidence for the primary role of humoral immunity, passive transfer with immunoglobulins from the two animal models and human ALS was carried out. Mice injected with serum or immunoglobulins from the animal disease models and human ALS but not controls demonstrated IgG in motoneurons and at the neuromuscular junction. The mice also demonstrated an increase in miniature end-plate potential (mepp) frequency, with normal amplitude and time course and normal resting membrane potential, indicating an increased resting quantal release of acetylcholine from the nerve terminal. The ability to transfer motoneuron dysfunction with serum immunoglobulins provides evidence for autoimmune mechanisms in the pathogenesis of both the animal models and human ALS.

Full text

PDF
647

Images in this article

648Image
on p.648
648Image
on p.648
648Image
on p.648

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alnaes E., Rahamimoff R. On the role of mitochondria in transmitter release from motor nerve terminals. J Physiol. 1975 Jun;248(2):285–306. doi: 10.1113/jphysiol.1975.sp010974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Appel S. H., Engelhardt J. I., García J., Stefani E. Autoimmunity and ALS: a comparison of animal models of immune-mediated motor neuron destruction and human ALS. Adv Neurol. 1991;56:405–412. [PubMed] [Google Scholar]
  3. Atchison W. D., O'Leary S. M. BAY K 8644 increases release of acetylcholine at the murine neuromuscular junction. Brain Res. 1987 Sep 1;419(1-2):315–319. doi: 10.1016/0006-8993(87)90599-3. [DOI] [PubMed] [Google Scholar]
  4. Baeyens J. M., Del Pozo E. Comparison of the effects of calcium and the calcium channel stimulant Bay k 8644 on neomycin-induced neuromuscular blockade. Pharmacol Toxicol. 1989 Nov;65(5):398–401. doi: 10.1111/j.1600-0773.1989.tb01197.x. [DOI] [PubMed] [Google Scholar]
  5. Dreyer E. B., Kaiser P. K., Offermann J. T., Lipton S. A. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science. 1990 Apr 20;248(4953):364–367. doi: 10.1126/science.2326646. [DOI] [PubMed] [Google Scholar]
  6. Duncan C. J., Statham H. E. Interacting effects of temperature and extracellular calcium on the spontaneous release of transmitter at the frog neuromuscular junction. J Physiol. 1977 Jun;268(2):319–333. doi: 10.1113/jphysiol.1977.sp011859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Engelhardt J. I., Appel S. H. IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch Neurol. 1990 Nov;47(11):1210–1216. doi: 10.1001/archneur.1990.00530110068019. [DOI] [PubMed] [Google Scholar]
  8. Engelhardt J. I., Appel S. H., Killian J. M. Experimental autoimmune motoneuron disease. Ann Neurol. 1989 Sep;26(3):368–376. doi: 10.1002/ana.410260310. [DOI] [PubMed] [Google Scholar]
  9. Engelhardt J. I., Appel S. H., Killian J. M. Motor neuron destruction in guinea pigs immunized with bovine spinal cord ventral horn homogenate: experimental autoimmune gray matter disease. J Neuroimmunol. 1990 Apr;27(1):21–31. doi: 10.1016/0165-5728(90)90132-7. [DOI] [PubMed] [Google Scholar]
  10. Engelhardt J., Appel S. H. Motor neuron reactivity of sera from animals with autoimmune models of motor neuron destruction. J Neurol Sci. 1990 May;96(2-3):333–352. doi: 10.1016/0022-510x(90)90143-b. [DOI] [PubMed] [Google Scholar]
  11. Fabian R. H., Ritchie T. C. Intraneuronal IgG in the central nervous system. J Neurol Sci. 1986 May;73(3):257–267. doi: 10.1016/0022-510x(86)90150-4. [DOI] [PubMed] [Google Scholar]
  12. Fabian R. H. Uptake of plasma IgG by CNS motoneurons: comparison of antineuronal and normal IgG. Neurology. 1988 Nov;38(11):1775–1780. doi: 10.1212/wnl.38.11.1775. [DOI] [PubMed] [Google Scholar]
  13. García J., Engelhardt J. I., Appel S. H., Stefani E. Increased MEPP frequency as an early sign of experimental immune-mediated motoneuron disease. Ann Neurol. 1990 Sep;28(3):329–334. doi: 10.1002/ana.410280305. [DOI] [PubMed] [Google Scholar]
  14. HOREJSI J., SMETANA R. The isolation of gamma globulin from blood-serum by rivanol. Acta Med Scand. 1956 Jun 30;155(1):65–70. doi: 10.1111/j.0954-6820.1956.tb14351.x. [DOI] [PubMed] [Google Scholar]
  15. Katz B., Miledi R. The role of calcium in neuromuscular facilitation. J Physiol. 1968 Mar;195(2):481–492. doi: 10.1113/jphysiol.1968.sp008469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Katz B., Miledi R. Transmitter leakage from motor nerve endings. Proc R Soc Lond B Biol Sci. 1977 Feb 11;196(1122):59–72. doi: 10.1098/rspb.1977.0029. [DOI] [PubMed] [Google Scholar]
  17. Lamb G. D., Walsh T. Calcium currents, charge movement and dihydropyridine binding in fast- and slow-twitch muscles of rat and rabbit. J Physiol. 1987 Dec;393:595–617. doi: 10.1113/jphysiol.1987.sp016843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lang B., Newsom-Davis J., Wray D., Vincent A., Murray N. Autoimmune aetiology for myasthenic (Eaton-Lambert) syndrome. Lancet. 1981 Aug 1;2(8240):224–226. doi: 10.1016/s0140-6736(81)90474-8. [DOI] [PubMed] [Google Scholar]
  19. Rich K. M., Hollowell J. P. Flunarizine protects neurons from death after axotomy or NGF deprivation. Science. 1990 Jun 15;248(4961):1419–1421. doi: 10.1126/science.2356470. [DOI] [PubMed] [Google Scholar]
  20. Toyka K. V., Brachman D. B., Pestronk A., Kao I. Myasthenia gravis: passive transfer from man to mouse. Science. 1975 Oct 24;190(4212):397–399. doi: 10.1126/science.1179220. [DOI] [PubMed] [Google Scholar]
  21. Troost D., van den Oord J. J., de Jong J. M., Swaab D. F. Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis. Clin Neuropathol. 1989 Nov-Dec;8(6):289–294. [PubMed] [Google Scholar]
  22. Uchitel O. D., Appel S. H., Crawford F., Sczcupak L. Immunoglobulins from amyotrophic lateral sclerosis patients enhance spontaneous transmitter release from motor-nerve terminals. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7371–7374. doi: 10.1073/pnas.85.19.7371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Weiss J. H., Hartley D. M., Koh J., Choi D. W. The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity. Science. 1990 Mar 23;247(4949 Pt 1):1474–1477. doi: 10.1126/science.247.4949.1474. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES